Abstract
Background/Aim: In several studies, Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have been reported to increase hemoglobin (Hb) levels. In a study in which Hb levels were compared between patients who received SGLT2i and dipeptidyl peptidase-4 inhibitors, some patients exhibited increased Hb levels (>1.0 g/dl), whereas some exhibited unchanged Hb levels. Notably, several factors may influence the Hb-increasing effect of SGLT2i. This study aimed to analyze the factors influencing the Hb-increasing effect of SGLT2i. Patients and Methods: Type 2 diabetes patients were divided into three groups: SGLT2i (SGLT2i only group, n=36), those receiving a combination of SGLT2i and angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) (SGLT2i+ACEi/ARBs group, n=32), and those not receiving these drugs (control group, n=49). We retrospectively analyzed Hb changes in these groups. Kaplan-Meier curves compared Hb changes from SGLT2i initiation to day 63, with an Hb increase defined as ≥0.5 g/dl. In addition, sex, age, ACEi/ARBs, estimated glomerular filtration rate, and hematocrit levels were analyzed using Cox proportional hazards as factors influencing Hb-increasing events. Results: Hb-increasing event rates were 61%, 41%, and 20% in the SGLT2i only, SGLT2i+ACEi/ARBs, and control groups, respectively. The Kaplan-Meier curves showed significantly higher Hb-increasing event rates in the SGLT2i only group than in the control and SGLT2i+ACEi/ARBs groups. In the Cox proportional hazards model, ACEi/ARBs use was associated with a 39% reduction in the incidence of Hb-increasing events. Conclusion: SGLT2i exhibit a Hb-increasing effect, which may be reduced by ACEi/ARBs.
Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are oral hypoglycemic agents that increase urinary glucose excretion by inhibiting glucose reabsorption in the proximal renal tubules (1). In addition to lowering glucose levels, SGLT2i induce hematopoietic effects, weight loss, and cardio-renal protection (2-5). SGLT2i have been used to induce cardiorenal protection in patients with chronic heart failure and chronic kidney disease (CKD) (6, 7).
Neuropathy, retinopathy, and nephropathy are the three major complications of type 2 diabetes mellitus (T2DM). Diabetic nephropathy occurs in 30-40% of patients with T2DM (8). Furthermore, renal anemia, a complication of diabetic nephropathy, worsens the prognosis of cardiovascular diseases and increases the mortality rate (9-11). In studies on SGLT2i use in patients with T2DM, significant increases in hemoglobin (Hb) and hematocrit (Hct) levels were observed in the SGLT2i group than in the placebo group (3, 12, 13). In addition, in the CREDENCE study on patients with T2DM who developed CKD, canagliflozin, an SGLT2i, reduced the incidence of anemia by 42% (14). In a previous study in which Hb levels were compared between patients who received SGLT2i and dipeptidyl peptidase-4 inhibitors, a difference of 1.9 g/dl was observed after 90 days (p<0.001) (15). Therefore, SGLT2i are considered to increase Hb levels. Notably, they are also associated with a reduced risk of anemia.
Epidemiological studies on anemia and heart failure reported an estimated 16% increase in the prevalence of anemia between 1979, before the discovery of renin-angiotensin-aldosterone system (RAAS) inhibitors, and 2002, when RAAS inhibitors became the standard treatment (16). In a study in which the effect of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs) on anemia was examined in patients with normal or mildly low glomerular filtration rate, the mean Hb level was significantly reduced by 0.41 g/dl in the ACEi/ARBs group compared with the placebo group (17). In studies on patients with T2DM and CKD treated with losartan, an ARB, a decrease of 0.6 g/dl was observed in the Hb level from the baseline value while maintaining renal protection (18).
Angiotensin II stimulates erythroid progenitor cells in the RAAS, which is the site of action of ACEi/ARBs (19, 20). In addition, angiotensin II induces renal tubuloplasmic hypoxia, stimulating the hypoxia-inducible factor (HIF), which promotes endogenous erythropoietin (EPO) secretion and erythropoiesis (21). This suggests that RAAS inhibition reduces Hb levels.
Therefore, ACEi/ARBs use may influence the Hb-increasing effect of SGLT2i. However, the effects of SGLT2i, which increase Hb levels, and RAAS inhibitors, which decrease Hb levels, in patients with hypertension and diabetes are unknown. In this study, we aimed to explore the factors influencing the Hb-increasing effect of SGLT2i, particularly ACEi/ARBs use.
Patients and Methods
Study participants and design. The participants were Japanese outpatients with T2DM who visited the International University of Health and Welfare Hospital between April 2021 and September 2023. The selected patients were divided into three groups: SGLT2i only, SGLT2i+ACEi/ARBs, and control groups. The ACEi used were enalapril, perindopril, and erbumin and the ARBs used were azilsartan, olmesartan, telmisartan, and losartan. The control group did not receive SGLT2i and ACEi/ARBs but received alogliptin, sitagliptin, linagliptin, teneligliptin, and vildagliptin. Informed consent was not obtained because this was a retrospective, noninterventional study. The opt-out document for this study was made publicly available. This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board and Ethics Committee of the International University of Health and Welfare (approval no.24-TA-005).
Patients taking iron supplements, erythropoiesis-stimulating agents (ESAs), or HIF prolyl hydroxylase (HIF-PH) inhibitors, those with heart failure or suspected of having heart failure, those who had received a blood transfusion within the previous 30 days, those with an estimated glomerular filtration rate (eGFR) ≤30 ml/min, and those who had discontinued SGLT2i or ACEi/ARBs within the previous 30 days were excluded from the study.
Hb levels were monitored at baseline and at least once a month, from 1-63 days after the initiation of SGLT2i or control medication. An increase of ≥0.5 g/dl in Hb level was defined as a Hb-increasing effect and was evaluated as the primary outcome (3, 15). Renal function was assessed based on the eGFR for Japanese individuals and calculated using the following formula: 194×(serum creatinine level)-1.094×age-0.287 (×0.739 for women) (22).
Statistical analysis. Continuous variables are presented as mean±standard deviation. Continuous variables were analyzed using the unpaired Student’s t-test, and frequency data were analyzed using the chi-square test, with p-values indicated. A two-tailed risk rate<5% was considered statistically significant.
Kaplan-Meier curves were drawn to compare Hb trends among the SGLT2i only, SGLT2i+ACEi/ARBs, and control groups, and log-rank tests were performed. For the Cox proportional hazards model, the objective variable was indicated based on an increase in the Hb level above 0.5 g/dl. The explanatory variables were selected based on the following criteria: p-value <0.2 in univariate regression analysis or factors considered to influence changes in Hb level, including sex, age, ACEi/ARBs, eGFR, and Hct. All calculations were performed using the Bell Curve for Excel (version 4.06; Social Research and Information, Inc., Tokyo, Japan).
Results
Figure 1 shows the patient flow chart of this study. Between April 2021 and September 2023, 466 patients underwent SGLT2i treatment. Of them, 398 patients were excluded because of insufficient Hb data, and the remaining 68 patients were finally analyzed. The SGLT2i only and SGLT2i+ACEi/ARBs groups comprised 36 and 32 patients, respectively. Of the patients with T2DM receiving outpatient therapy during the same period, 49 who did not receive SGLT2i or ACEi/ARBs were selected as controls.
Patient flowchart. The extraction and exclusion processes of patient data in this retrospective survey are shown.
Table I presents the patient backgrounds of each group. Patients in the SGLT2i only group were significantly younger than those in the control group. Hb levels increased by >0.5 g/dl in 22 (61%) patients in the SGLT2i only group compared with only 13 (41%) and 10 (20%) patients in the SGLT2i+ACEi/ARBs and control groups, respectively.
Comparison of patient characteristics among the SGLT2i only, SGLT2i+ACEi/ARBs, and control groups.
Kaplan-Meier curves showed significantly higher Hb-increasing event rates in the SGLT2i group than in the control (p<0.001; Figure 2) and SGLT2i+ACEi/ARBs (p<0.02; Figure 3) groups. According to the Cox proportional hazards model, ACEi/ARBs use reduced the incidence of Hb-increasing events by 39% [odds ratio (OR)=0.608, 95% confidence interval (CI)=0.383-0.966, p=0.035] (Table II). In addition, men had a 1.85-fold higher rate of Hb-increasing events than women (OR=1.850, 95%CI=1.152-2.972, p=0.011).
Curve of cumulative rate of increase of hemoglobin in the sodium-glucose co-transporter-2 inhibitors and control groups.
Curve of the cumulative rate of increase of hemoglobin in the groups with and without angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.
Factors influencing the Hb-increasing effect of SGLT2i according to the Cox proportional hazards model.
Discussion
In this study, SGLT2i increased HB levels by >0.5 g/dl in 39% of patients. Only 20% of the patients in the control group had an increase of ≥0.5 g/dl in the Hb level. These results indicate the Hb-increasing effect of SGLT2i. Furthermore, the combination of SGLT2i and ACEi/ARBs reduced the rate of Hb-increasing events by 20%. In the control group, there were 35 patients who received concomitant ACEi/ARBs. Among them, three (9%) exhibited a decrease in Hb levels from the normal value to <12 g/dl. According to the Cox proportional hazards model, ACEi/ARBs use reduced the Hb-increasing effect of SGLT2i.
The following discussion provides evidence to increase the reliability of these data. In the Cox proportional hazards model, no association was observed between the increase in Hb level above 0.5 g/dl and eGFR or Hct level. This result suggests that the Hb-increasing effect of SGLT2i is a pharmacological effect of SGLT2i rather than a relative increase due to fluid enrichment. In this study, sex was identified as a factor influencing the Hb-increasing effect of SGLT2i. Approximately 80% of the patients with increased Hb levels were men. This may be due to the effect of testosterone (23). To the best of our knowledge, this is the first study to identify the factors influencing the Hb-increasing effect of SGLT2i.
Figure 4 shows the mechanism underlying the Hb-increasing effect of SGLT2i. Approximately 2 weeks after the initiation of SGLT2i therapy, a temporary decrease in renal function was observed. SGLT2i reduce kidney stress and restore EPO production capacity (24).
Mechanisms underlying the Hb-increasing effect of SGLT2i. ACE: Angiotensin converting enzyme inhibitors; ARB: Angiotensin II receptor blocker; AT1R: Angiotensin II type 1 receptor; SGLT2i: sodium glucose co-transporters; RAAS: renin angiotensin-aldosterone system.
Subsequently, kidney stress improves as tubular transport and glucose metabolism decrease (25). Furthermore, in studies on non-diabetic rats with renal anemia treated with ruseogliflozin, an SGLT2i, neither hematopoietic effects nor direct stimulation of EPO were observed (26). In a study on iron metabolism involving dapagliflozin, an SGLT2i, in obese patients with T2DM, dapagliflozin reduced the level of hepcidin, an iron-metabolizing hormone. Therefore, iron utilization and hematopoietic response improved (27). There is evidence that this effect may extend beyond the kidney to the liver and bone marrow. Therefore, the detailed mechanism underlying the Hb-increasing effect of SGLT2i remains unknown.
Hb level is an important management indicator of heart failure and CKD. Anemia and iron deficiency are considered poor prognostic factors in patients with heart failure and mildly reduced left ventricular ejection fraction (28). In patients with CKD, a 0.5 g/dl decrease in Hb level is associated with a 32% increase in the risk of left ventricular hypertrophy, and a 1.0 g/dl increase in Hb level reduces the risk of requiring renal replacement therapy by 26% (29). Therefore, the Hb-increasing effect of SGLT2i has an important clinical significance for the prognosis of patients with heart failure and may significantly affect patients with CKD and renal anemia. The offsetting effect of ACEi/ARBs on the beneficial Hb-increasing effect of SGLT2i may be clinically important.
Among the patients using SGLT2i in the present study, one (3%) had suspected secondary polycythemia vera. In addition, four (6%) patients with suspected secondary polycythemia vera in a study that included 31 patients with heart failure were excluded from the present study. Polycythemia vera causes thrombosis, including myocardial and cerebral infarction (30). While SGLT2i induce a positive Hb-increasing effect, they should also be used with caution in patients with polycythemia vera, which is characterized by excessive Hb. In particular, attention should be paid to polycythemia secondary to the concomitant use of SGLT2i with ESAs and HIF-PH inhibitors, which have potent hematopoietic effects (31, 32).
Study limitations. First, this was a single-center retrospective study. Second, the study population was heterogeneous. The mean age of patients in the SGLT2i group was lower than that of those in the control group. The lower mean age of patients in the SGLT2i group may have resulted in higher Hb levels. Age is associated with anemia, renal function, and hematopoietic capacity, which may have influenced our results. Third, the drug type and dose of ACEi/ARBs were not considered as factors influencing the Hb-increasing effect. Regarding ACEi, enalapril and perindopril erbumine were used, with ACE inhibition constants of 1.0 and 1.7 nM, respectively. The binding constants of telmisartan, a non-competitive antagonist, and losartan, a competitive antagonist, to the angiotensin II type 1 receptor differ at 20 nM and 3 nM, respectively (33, 34). In addition, the difference in half-life between losartan and telmisartan is >20 h (35). The same ACEi/ARBs may demonstrate a change in the Hb-increasing effect due to differences in pharmacokinetics.
In the future, it will be necessary to understand how pharmacokinetic and pharmacodynamic differences between ACEi/ARBs affect the increase in Hb levels caused by SGLT2 inhibitors. It is then necessary to select ACEi/ARBs that do not affect Hb variability in clinical practice.
Conclusion
SGLT2i exhibit a Hb-increasing effect, which may be reduced by ACEi/ARBs.
Acknowledgements
The Authors are grateful to Dr. Shunichiro Onishi for useful discussions. and Dr. Naoto Suzuki for carefully proofreading the manuscript.
Footnotes
Authors’ Contributions
Conceptualization; J. Sato; Data curation; Y. Yoshida; Formal analysis; Y. Yoshida; Investigation; Y. Yoshida; Methodology; J. Sato; Project administration; Y. Yoshida; Resources; Y. Yoshida, J. Sato; Supervision; J. Sato; Roles/Writing - original draft; Y. Yoshida, H. Yamada, J. Sato Writing - review & editing; Y. Yoshida, H. Yamada, J. Sato.
Conflicts of Interest
The Authors have no conflicts of interest with any companies related to this study that should be disclosed.
- Received July 5, 2024.
- Revision received July 27, 2024.
- Accepted July 29, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
